Rac GTPase inhibition in Chronic Myelogenous Leukemia. Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease with deregulated expression of the fusion gene p210-BCR-ABL. P210-BCR-ABL is needed to initiate and maintain CML. Molecular targeting of p210-BCR-ABL by inhibiting the abl kinase activity can suppress growth and induces apoptosis of CML cells. However, Abl kinase inhibitors are not able to eradicate the disease and alternatives targeting signaling downstream of p210-BCR-ABL in HSC/P are required. Since dysregulated Rac activity has been implicated in cancer transformation (and we have previously shown the role of Rac1 and Rac2 Rho GTPases in regulating proliferation, stem cell localization and apoptosis of HSC/P), we hypothesize that full p210-BCR-ABL mediated transformation of hematopoietic stem cells requires Rac activity and that Rac GTPase isoforms play distinct roles in the initiation and/or maintenance of p210-BCR- ABL-induced leukemia. By taking advantage of gene-targeted mice lacking Rac1, Rac2 and Rac3 and a pharmacological approach in vitro and in vivo in murine and human disease, we have generated preliminary data to indicate that Rac proteins play an essential role in the leukemogenic effects of p210-BCR-ABL in vitro and in vivo. In Specific Aim 1, we will investigate the requirement of the Rho GTPases Rac1, Rac2 and Rac3, or combinations in vitro and in vivo in leukemia initiation and in cell transformation. We will also investigate the role of Rac effectors and downstream signals in leukemia initiation. In Specific Aim 2, we will analyze whether Rac (and specific Rac isoforms) play distinct or redundant roles in the maintenance of leukeminas induced by p210-BCR-ABL. Finally, we will analyze whether the downstream signals activated by Rac for leukemic maintenance are different from the ones required for initiation. The results obtained from this project will validate the potential role of Rac GTPases as novel molecular targets for CML and dissect out the signals induced by Rac activation required for leukemogenesis and potential new targets for leukemic therapy. PUBLIC HEALTH RELEVANCE: Chronic myelogenous leukemia is a disease caused by the expression of an abnormal protein called BCR/ABL. Rac GTPases are a group of proteins that act as molecular switches in the cells. We will analyze whether Rac GTPases are critical for the development of leukemias induced by BCR/ABL and analyze the specific mechanisms depending on Rac GTPases responsible for leukemia formation.